ArticleNature genetics2020
Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.
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Article in Nature genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29citing papers in PubMed
1.9field-weighted citation impact, top 13% of its field
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
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- Regeneration alters open chromatin andGenome research · 2025Article
- Epigenetic Regulation of Erythropoiesis: From Developmental Programs to Therapeutic Targets.International journal of molecular sciences · 2025Review
- Harnessing endogenous miRNA targeting ZIKV: A cutting-edge strategy to inhibit virus infection.Molecular therapy. Nucleic acids · 2025Article
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- Enhancing disease risk gene discovery by integrating transcription factor-linked trans-variants into transcriptome-wide association analyses.Nucleic acids research · 2025Article
- INSIGHTS INTO ACUTE KIDNEY INJURY AND TRANSITION TO CHRONIC KIDNEY DISEASE BY SINGLE-CELL TECHNOLOGIES.Transactions of the American Clinical and Climatological Association · 2025Review
- Multiome-wide Association Studies: Novel Approaches for Understanding Diseases.Genomics, proteomics & bioinformatics · 2024Review
- An RNA-centric view of transcription and genome organization.Molecular cell · 2024Review
- Role of RNA modifications in blood development and regeneration.Experimental hematology · 2024Review
- Tracing post-domestication historical events and screening pre-breeding germplasm from large gene pools in wheat in the absence of phenotype data.TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik · 2024Article
- Cell fate decision in erythropoiesis: Insights from multiomics studies.Experimental hematology · 2024Review
- Chromatin priming elements direct tissue-specific gene activity before hematopoietic specification.Life science alliance · 2024Article
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- PGEProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks.The Journal of clinical investigation · 2023Article
- Whole-genome functional characterization of RE1 silencers using a modified massively parallel reporter assay.Cell genomics · 2023Article
Corrections and comments
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Authors and funding
33 authors at 11 institutions in 5 countries.
Avik Choudhuri *Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Eirini Trompouki *Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7242-8810
Brian J Abraham *Whitehead Institute for Biomedical Research, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8085-3027
Leandro M ColliDivision of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, USA.
Kian Hong KockDivision of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
William MallardHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2271-945X
Min-Lee YangDivision of Cardiovascular Medicine, Department of Internal Medicine and Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Divya S VinjamurDivision of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9369-0412
Alireza GhamariDivision of Pediatric Hematology-Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Audrey SporrijHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Karen HoiHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Barbara HummelDepartment of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Sonja BoatmanStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Victoria ChanHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Sierra TsengHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Satish K NandakumarDivision of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7853-426X
Song YangStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Asher LichtigStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Michael SuperdockStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0003-4165-4425
Seraj N GrimesDivision of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Teresa V BowmanStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Yi ZhouStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Shinichiro TakahashiTohoku Medical and Pharmaceutical University, Sendai, Japan.
Roby JoehanesHebrew Senior Life, Harvard Medical School, Boston, MA, USA.
Alan B CantorDivision of Pediatric Hematology-Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Daniel E BauerDivision of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5076-7945
Santhi K GaneshDivision of Cardiovascular Medicine, Department of Internal Medicine and Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
John RinnHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Paul S AlbertDivision of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, USA.
Martha L BulykDivision of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Stephen J ChanockDivision of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-2324-3393
Richard A YoungWhitehead Institute for Biomedical Research, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8855-8647
Leonard I ZonHarvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. zon@enders.tch.harvard.edu.ORCID http://orcid.org/0000-0003-0860-926X
Boston Children's Hospital · USHarvard University · USNational Cancer Institute · USBrigham and Women's Hospital · USBroad Institute · USUniversity of Michigan · USHoward Hughes Medical Institute · USMax Planck Institute of Immunobiology and Epigenetics · DESt. Jude Children's Research Hospital · USTohoku Medical and Pharmaceutical University · JPWhitehead Institute for Biomedical Research · US
Funding
TRANSCRIPTION FACTOR GATA-1 IN TERMINAL ERYTHROID DEVELOPMENTP01HL032262 · NHLBI · CHILDREN'S HOSPITAL BOSTON · PI ORKIN, STUART H · 1985 to 2021
$38.9MTargeting Genomic Instability and Evolution in MyelomaP01CA155258 · NCI · DANA-FARBER CANCER INST · PI Nikhil C. Munshi · 2011 to 2026
$32.5MGenome-Wide Association Analysis in Essential Hypertension (FEHGAS study)R01HL086694 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ARAVINDA CHAKRAVARTI · 2007 to 2026
$21.2MCORE--ZEBRAFISHP30DK049216 · NIDDK · CHILDREN'S HOSPITAL BOSTON · PI ZHOU, YI · 1999 to 2015
$14.3MCustomized stem cells for clinical application in blood disordersR24DK092760 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI COLLINS, JAMES J, DALEY, GEORGE Q · 2011 to 2018
$10.7MStem cells for therapeutics discovery in genetic blood disordersU01HL134812 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI DALEY, GEORGE Q, LIPTON, JEFFREY M · 2016 to 2022
$8.3MMolecular Circuits in the Hematopoietic Stem Cell NicheRC2DK120535 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI COLLINS, JAMES J, DALEY, GEORGE Q · 2020 to 2024
$8.2MA Community Zebrafish Resource for Modeling GWAS BiologyR24OD017870 · OD · BRIGHAM AND WOMEN'S HOSPITAL · PI GOESSLING, WOLFRAM, MACRAE, CALUM A. · 2014 to 2021
$6.3MCOMPARATIVE APPROACH TO GLOBIN REGULATION/THALASSEMIAR01DK053298 · NIDDK · CHILDREN'S HOSPITAL BOSTON · PI ZON, LEONARD IRA · 1998 to 2012
$3.9MTranscriptional regulatory networks in living cellsR01GM123511 · NIGMS · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI YOUNG, RICHARD · 2017 to 2020
$3.6MGenetic Studies of The Impact of Hematologic Traits On Cardiovascular DiseaseR01HL122684 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GANESH, SANTHI K · 2015 to 2019
$3.4MTargeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung CancerU01CA213333 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI GRAY, NATHANAEL SCHIANDER, WONG, KWOK KIN · 2017 to 2021
$3.3MHoward Hughes Medical InstituteNCI NIH HHS P01 CA155258NCI NIH HHS U01 CA213333NHGRI NIH HHS R21 HG010200NHLBI NIH HHS DP2 HL137300NHLBI NIH HHS N01 HC025195NHLBI NIH HHS P01 HL032262NHLBI NIH HHS R01 HL086694NHLBI NIH HHS R01 HL122684NHLBI NIH HHS R01 HL139672NHLBI NIH HHS R01 HL144780NHLBI NIH HHS U01 HL134812NIDDK NIH HHS P30 DK049216NIDDK NIH HHS R01 DK053298NIDDK NIH HHS R24 DK092760NIDDK NIH HHS RC2 DK120535NIGMS NIH HHS R01 GM123511NIH HHS R24 OD017870
Abstract
Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-β-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.
Indexed as
PhenotypeDNA-Binding ProteinsEnhancer Elements, GeneticErythrocytesGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansPolymorphism, Single NucleotideQuantitative Trait LociSmad1 ProteinTranscription FactorsTranscription, GeneticDNA-Binding ProteinsSmad1 ProteinSMAD1 protein, humanTranscription Factors
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